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Cytoplasmic pFOXO3a expression is associated with sentinel node metastasis in HER2-positive breast cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Department of Oncology, Örebro University Hospital, SE-70185 Örebro, Sweden.
Clinical Research Centre, Örebro University Hospital, SE-70185 Örebro, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Breast cancers with human epidermal growth factor receptor (HER) 2 gene amplification or protein overexpression (HER2+ breast cancer) is associated with poor prognosis. Activated HER2 receptors dimerise and activate the oncokinase Akt; which phosphorylate the tumour suppressor protein Forkhead box O3a (FOXO3a), repressing its transcriptional activity. Oncogenic FOXG1 can act as a transcriptional repressor for genes which are transcriptionally activated by FOXOs and phosphorylation of FOXG1 via Akt causes its nuclear export in differentiated cells. To better understand the AKT/FOXO3a/FOXG1 connection and their clinical relevance, we investigated the expression and localisation of pAkt, pFOXO3a and FOXG1 in HER2+ breast cancer.

Methods: Immunohistochemical analysis was performed to determine the expression and localisation of pAkt, pFOXO3a and FOXG1 on tissue microarray constructs from HER2+ primary breast tumours (n=91) and their relation to clinic pathological parameters were analysed.

Results: Nuclear expression of pAkt was found to be correlated to nuclear (p<0.001) as well as cytoplasmic expression of pFOXO3a (p = 0.006), while cytoplasmic expression of pAkt was found to be correlated to cytoplasmic expression of pFOXO3a (p<0.001). Nuclear expression of pFOXO3a was inversely correlated to cytoplasmic expression of FOXG1 (p=0.003). Cytoplasmic expression of pFOXO3a was found to be associated with sentinel node metastasis (p=0.011), while cytoplasmic FOXG1 expression was correlated to negative progesterone receptor status (p=0.008).

Conclusion: Our results suggest that the expression and localisation of pAkt and pFOXO3a is interconnected, while the expression of FOXG1 is connected to pFOXO3a. Our findings indicate the biological value of expression as well as localisation of these proteins in HER2+ breast cancer.

Keywords [en]
HER2+ breast cancer, pAkt, pFOXO3a, FOXG1, Immunohistochemistry
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-29135OAI: oai:DiVA.org:oru-29135DiVA, id: diva2:622604
Available from: 2013-05-22 Created: 2013-05-22 Last updated: 2017-10-17Bibliographically approved
In thesis
1. Biological signature of HER2-positive breast cancer
Open this publication in new window or tab >>Biological signature of HER2-positive breast cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human epidermal growth factor receptor 2 (HER2) overexpressing breast cancers (HER2+ breast cancer) are associated with an aggressive disease course. This thesis is focused on improving the understanding of the biological signature of HER2+ breast cancer.

In Paper I, we identified a common deletion spanning the SLC25A43 gene which codes for a mitochondrial transport protein. Loss of heterozygosity in this gene was confirmed in an extended cohort of HER2+ breast cancer and in other types of cancers. Protein expression analysis of SLC25A43using immunohistochemistry (IHC) in HER2+ breast cancers showed that tumours with negative or low expression of SLC25A43 had lower S-phase fraction compared to tumours with medium or high expression, indicating its possible role in cell proliferation. Absence of mutations in this gene in HER2+ breast cancers led to Paper II where DNA methylation in the SLC25A43 gene was interrogated using Pyrosequencing. HER2+ breast cancer with no deletion in the SLC25A43 gene showed higher methylation in the CpG island (CGI), suggesting methylation in the CGI as an alternate mechanism for SLC25A43 gene inactivation. Methylation in the CGI and in the adjacent shores of the SLC25A43 gene was associated with negative oestrogen receptor status and positive lymph node status. In Paper III, genome-wide DNA methylation analysis of HER2+ breast cancer and normal breast tissue revealed hypermethylation in HER2+ breast cancer affecting particularly the homeobox gene family when compared to normal. We identified a total of 73 candidate genes showing differential methylation in HER2+ breast cancer and external validation of gene expression in a selected group of these genes revealed lowered mean expression in HER2+ breast cancer, warranting future clinical studies of these candidate genes. In Paper IV, we investigated expression and localisation of phosphorylated (p) Akt and FOXO3a and FOXG1 in HER2+ breast cancer using IHC. Cytoplasmic expression of pFOXO3a was associated with sentinel node metastasis while cytoplasmic expression of FOXG1 was correlated to negative progesterone receptor status. This indicates the biological and prognostic value of these proteins in HER2+ breast cancer.

Thus, this thesis identified changes at the genetic, epigenetic and protein levels which add new information and improve our understanding of HER2+ breast cancer.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 61
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 90
Keywords
HER2+ breast cancer, SLC25A43, CpG island, DNA methylation, Homeobox genes, FOXO3a, FOXG1
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-28978 (URN)978-91-7668-941-7 (ISBN)
Public defence
2013-06-14, Wilandersalen, F-huset, Örebro universitetssjukhus, Södra Grev Rosengatan, Örebro, 11:00 (Swedish)
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Supervisors
Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2018-03-09Bibliographically approved

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